CN104892441A - Method for preparing pregabalin isomer R-pregabalin - Google Patents
Method for preparing pregabalin isomer R-pregabalin Download PDFInfo
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- CN104892441A CN104892441A CN201510264661.XA CN201510264661A CN104892441A CN 104892441 A CN104892441 A CN 104892441A CN 201510264661 A CN201510264661 A CN 201510264661A CN 104892441 A CN104892441 A CN 104892441A
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Abstract
The invention discloses a method for preparing a pregabalin isomer R-pregabalin. The method comprises the following steps: resolving 3-isobutylglutaryl amine with R-phenylethylamine to obtain a mother solution concentrate, and freeing by adding water and hydrochloric acid; adding ethyl acetate into the obtained free product for refinement, and drying to obtain S-3-isobutylglutaryl amine; adding the S-3-isobutylglutaryl amine into a liquid alkali system, dropwisely adding bromine, heating to a certain temperature, and cooling; dropwisely adding hydrochloric acid to regulate the pH value to 6-8, and cooling to crystallize to obtain an R-pregabalin crude product; and adding the R-pregabalin into an isopropanol-water system, heating to a certain temperature, stirring while keeping the temperature, cooling to a certain temperature to crystallize, carrying out vacuum filtration, and drying to obtain the R-pregabalin. The preparation method is economical and simple, and can obtain the high-purity R-pregabalin at high yield without special reagents or reaction conditions.
Description
Technical field
The invention provides a kind of method preparing lyrica isomer R-lyrica, belong to field of medicine and chemical technology.
background of invention
Neurogenic pain refers to the pain because neural system sustains damage or produces pathology and cause, with dull pain, scorching hot, shouting pain for principal character.According to estimates, the whole world about has the population of 1% to be subject to the puzzlement of this kind of disease.Epilepsy is the too high and paradoxical discharge that causes of brain neuroblastoma unit excitability, is brain disorders syndrome.According to World Health Organization's statistics, global epileptic's sum is up to more than 5,000 ten thousand, and only China has just exceeded 6,000,000, and sickness rate is about 5/1000ths.Research finds, a lot of antiepileptic drug has analgesic effect simultaneously.
Lyrica (trade(brand)name: Lyrica), chemistry (3S)-3-aminomethyl-5-methylhexanoic acid by name, it is γ-aminobutyric acid (GABA) receptor antagonist developed by Warner-Lambert company, within 2003, in the U.S., application for registration is proposed by Pfizer, in December, 2004, FDA ratifies lyrica as the medicine listing for the treatment of diabetic neuralgia and herpes zoster neuralgia.Lyrica is first medicine being simultaneously applicable to treat above-mentioned two kinds of pain of US and European accreditation.In June, 2005, lyrica is granted for assisting therapy grownup partial onset epilepsy.Generalized anxiety disorder and fibromyalgia syndrome etc. are treated in approval successively afterwards.Within 2007, lyrica is chosen as one of " large medical advance in 2007 ten " by the U.S.'s " epoch " weekly.
Only have the lyrica of S configuration to have pharmacological action, and R configuration does not have drug effect, so prepare less containing R configuration or prepare being necessary very much as standard substance or reference substance of R configuration.And reported literature seldom has the article describing lyrica isomer at present.
Summary of the invention
The object of this invention is to provide a kind of method preparing the preparation of lyrica isomer R-lyrica, comprise the following steps:
1) 3-isobutylglutaric acid monoamide is used the mother liquor concentrations thing after the fractionation of R-phenylethylamine, add water free with hydrochloric acid;
2) educt obtained above is added ethyl acetate refining, dry and obtain S-3-isobutylglutaric acid monoamide;
3) S-3-isobutylglutaric acid monoamide is dropped in liquid caustic soda system, drip bromine, lower the temperature again after rising to certain temperature;
4) start to drip hydrochloric acid and adjust pH to 6 ~ 8, be cooled to 0 ~ 10 DEG C of crystallization and obtain R-lyrica crude product;
5) dropped into by R-lyrica in the system of isopropyl alcohol and water, rise to certain temperature insulated and stirred, then be down to certain temperature crystallization, suction filtration is dried and is obtained R-lyrica;
Mother liquor concentrations thing after R-phenylethylamine described in step 1) splits refers to and add compound 3-isobutylglutaric acid monoamide in chloroform and alcohols mixed system, drips suction filtration after resolving agent R-phenylethylamine splits and also filtrate is concentrated the dry mother liquor concentrations thing obtained.
The weight that described step 1) adds water is 1 ~ 2 times of enriched material weight, and the amount of hydrochloric acid is as the criterion with pH, and pH is 1 ~ 4;
Described step 2) weight of ethyl acetate is 1 ~ 4 times of wet product S-3-isobutylglutaric acid monoamide weight;
Described step 2) educt adds the molten clear temperature of ethyl acetate in treating process is 40 ~ 45 DEG C, and the temperature of stirring and crystallizing is 0 ~ 10 DEG C afterwards;
The liquid caustic soda weight that described step 3) adds is 2 ~ 4 times of S-3-isobutylglutaric acid monoamide weight;
The weight of described step 3) bromine is 0.7 ~ 0.9 times of S-3-isobutylglutaric acid monoamide weight;
Described step 3) rises to certain temperature and refers to 70 ~ 80 DEG C, is down to certain temperature and refers to 20 ~ 30 DEG C;
Described step 5) Virahol: water: the weight ratio of lyrica crude product three is 8:4:1 ~ 2:2:1;
Described step 5) is warming up to certain temperature and refers to 70 ~ 80 DEG C, is down to certain temperature crystallization and refers to 0 ~ 10 DEG C, and the time of insulation crystallization refers to 1 ~ 2 hour.
The invention provides an economy, simply prepare the preparation method of lyrica isomer R-lyrica, do not need special reagent and reaction conditions can obtain highly purified R-lyrica.
Embodiment
Below in conjunction with example, the present invention is further elaborated, but these examples do not form any restriction to the present invention.
Split the preparation method of mother liquor:
Take 100g 3-isobutylglutaric acid monoamide, 1500g chloroform and 20g ethanol are warming up to 40 ~ 55 DEG C, stir lower dropping R-phenylethylamine 45g, dropwise rear insulation 30min, then be cooled to 25 DEG C, insulated and stirred 1 hour, namely concentrated for filtrate doing be mother liquor concentrations thing by suction filtration.
Wherein, the deprotected chemical displacement of R-lyrica is as follows: 0.78 ~ 0.81 (t; 1,2; 6H), 1.11 ~ 1.13 (d; 4,2H), 1.54 ~ 1.58 (m; 3; 1H), 2.01 ~ 2.10 (m; 5; 1H), 2.12 ~ 2.24 (dd; 7; 2H), 2.84 ~ 2.93 (dd; 6; 2H).MS：m/z=160。
Example 1:
Mother liquor concentrations thing 100g will be split, add water 100g, stir lower dropping hydrochloric acid and adjust pH to 2, suction filtration obtains educt 65g, ethyl acetate 150g is added in wet product, be warming up to 40 DEG C molten clear after be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained S-3-isobutylglutaric acid monoamide 53g, and yield is 75%.The S-3-isobutylglutaric acid monoamide 30g of oven dry is added in the four-hole boiling flask of 500ml, liquid caustic soda 65g, 25g bromine is dripped at being cooled to 10 DEG C, be warming up to 75 DEG C of insulations after dropwising and be cooled to 20 DEG C afterwards in 2 hours, start to drip hydrochloric acid and adjust pH to 7, then be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained R-lyrica crude product 20g, yield 78%.Take the lyrica crude product 20g of will dry, Virahol and water are respectively 100g and 50g, start to be cooled to 0 ~ 10 DEG C of insulated and stirred 1h after being warming up to 80 DEG C, and suction filtration is dried and obtained R-lyrica 18g, purity 99.8%, isomer 0.01%, and yield is 90%.
Example 2:
Mother liquor concentrations thing 100g will be split, add water 150g, stir lower dropping hydrochloric acid and adjust pH to 2, suction filtration obtains educt 60g, ethyl acetate 180g is added in wet product, be warming up to 40 DEG C molten clear after be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained S-3-isobutylglutaric acid monoamide 55g, and yield is 78%.The S-3-isobutylglutaric acid monoamide 30g of oven dry is added in the four-hole boiling flask of 500ml, liquid caustic soda 75g, 30g bromine is dripped at being cooled to 10 DEG C, be warming up to 80 DEG C of insulations after dropwising and be cooled to 30 DEG C afterwards in 2 hours, start to drip hydrochloric acid and adjust pH to 7, then be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained R-lyrica crude product 21g, and yield is 84%.Take the lyrica crude product 22g of will dry, Virahol and water are respectively 90g and 45g, start to be cooled to 0 ~ 10 DEG C of insulated and stirred 1.5h after being warming up to 80 DEG C, and suction filtration is dried and obtained R-lyrica 18.2g, purity 99.9%, isomer 0.02%.Yield is 82.7%.
Example 3:
Mother liquor concentrations thing 100g will be split, add water 150g, stir lower dropping hydrochloric acid and adjust pH to 3, suction filtration obtains educt 68g, ethyl acetate 140g is added in wet product, be warming up to 40 DEG C molten clear after be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained S-3-isobutylglutaric acid monoamide 54g, and yield is 74.3%.The S-3-isobutylglutaric acid monoamide 30g of oven dry is added in the four-hole boiling flask of 500ml, liquid caustic soda 75g, 24g bromine is dripped at being cooled to 10 DEG C, be warming up to 75 DEG C of insulations after dropwising and be cooled to 30 DEG C afterwards in 2 hours, start to drip hydrochloric acid and adjust pH to 7, then be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained R-lyrica crude product 19.6g, and yield is 78.4%.Take the lyrica crude product 20g of will dry, Virahol and water are respectively 100g and 60g, start to be cooled to 0 ~ 10 DEG C of insulated and stirred 2h after being warming up to 80 DEG C, and suction filtration is dried and obtained R-lyrica 18.3g, purity 99.9%, isomer 0.01%, and yield is 91.5%.
Example 4:
Mother liquor concentrations thing 100g will be split, add water 100g, stir lower dropping hydrochloric acid and adjust pH to 1, suction filtration obtains educt 70g, ethyl acetate 150g is added in wet product, be warming up to 45 DEG C molten clear after be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained S-3-isobutylglutaric acid monoamide 58g, and yield is 82.1%.The S-3-isobutylglutaric acid monoamide 30g of oven dry is added in the four-hole boiling flask of 500ml, liquid caustic soda 90g, 24g bromine is dripped at being cooled to 10 DEG C, be warming up to 75 DEG C of insulations after dropwising and be cooled to 20 DEG C afterwards in 2 hours, start to drip hydrochloric acid and adjust pH to 8, then be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained R-lyrica crude product 20.5g, and yield is 82%.Take the lyrica crude product 20g of will dry, Virahol and water are respectively 150g and 50g, start to be cooled to 0 ~ 10 DEG C of insulated and stirred 1h after being warming up to 80 DEG C, and suction filtration is dried and obtained R-lyrica 18g, purity 99.7%, isomer 0.02%, and yield is 90%.
Example 5:
Mother liquor concentrations thing 100g will be split, add water 120g, stir lower dropping hydrochloric acid and adjust pH to 3, suction filtration obtains educt 63g, ethyl acetate 170g is added in wet product, be warming up to 40 DEG C molten clear after be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained S-3-isobutylglutaric acid monoamide 57g, and yield is 80.7%.The S-3-isobutylglutaric acid monoamide 30g of oven dry is added in the four-hole boiling flask of 500ml, liquid caustic soda 68g, 26g bromine is dripped at being cooled to 10 DEG C, be warming up to 75 DEG C of insulations after dropwising and be cooled to 20 DEG C afterwards in 2 hours, start to drip hydrochloric acid and adjust pH to 6, then be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained R-lyrica crude product 20.2g, and yield is 80.8%.Take the lyrica crude product 20g of will dry, Virahol and water are respectively 130g and 55g, start to be cooled to 0 ~ 10 DEG C of insulated and stirred 1.5h after being warming up to 80 DEG C, and suction filtration is dried and obtained R-lyrica 18.5g, purity 99.8%, isomer 0.01%, yield 92.5%.
Example 6:
Mother liquor concentrations thing 100g will be split, add water 180g, stir lower dropping hydrochloric acid and adjust pH to 1, suction filtration obtains educt 60g, ethyl acetate 120g is added in wet product, be warming up to 40 DEG C molten clear after be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained S-3-isobutylglutaric acid monoamide 52.3g, and yield is 74%.The S-3-isobutylglutaric acid monoamide 30g of oven dry is added in the four-hole boiling flask of 500ml, liquid caustic soda 80g, 25g bromine is dripped at being cooled to 10 DEG C, be warming up to 80 DEG C of insulations after dropwising and be cooled to 25 DEG C afterwards in 2 hours, start to drip hydrochloric acid and adjust pH to 8, then be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained R-lyrica crude product 20.0g, and yield is 80%.Take the lyrica crude product 20g of will dry, Virahol and water are respectively 140g and 60g, start to be cooled to 0 ~ 10 DEG C of insulated and stirred 2h after being warming up to 80 DEG C, and suction filtration is dried and obtained R-lyrica 17.9g, purity 99.8%, isomer 0.03%, and yield is 89.5%.
Example 7:
To split mother liquor concentrations thing 100g, add water 110g, stirs lower dropping hydrochloric acid and adjust pH to 3, suction filtration obtains educt 69g, in wet product, add ethyl acetate 158g, be warming up to 45 DEG C molten clear after be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained S-3-isobutylglutaric acid monoamide.The S-3-isobutylglutaric acid monoamide 30g of oven dry is added in the four-hole boiling flask of 500ml, liquid caustic soda 70g, 24g bromine is dripped at being cooled to 10 DEG C, be warming up to 75 DEG C of insulations after dropwising and be cooled to 20 DEG C afterwards in 2 hours, start to drip hydrochloric acid and adjust pH to 6, then be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained R-lyrica crude product.Take the lyrica crude product 20g of will dry, Virahol and water are respectively 50g and 50g, start to be cooled to 0 ~ 10 DEG C of insulated and stirred 2h after being warming up to 80 DEG C, and suction filtration is dried and obtained R-lyrica 18.3g, purity 99.9%, isomer N.D.
Example 8:
Mother liquor concentrations thing 100g will be split, add water 200g, stir lower dropping hydrochloric acid and adjust pH to 2, suction filtration obtains educt 65g, ethyl acetate 180g is added in wet product, be warming up to 40 DEG C molten clear after be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained S-3-isobutylglutaric acid monoamide 53.5g, and yield is 75.7%.The S-3-isobutylglutaric acid monoamide 30g of oven dry is added in the four-hole boiling flask of 500ml, liquid caustic soda 75g, 27g bromine is dripped at being cooled to 10 DEG C, be warming up to 75 DEG C of insulations after dropwising and be cooled to 20 DEG C afterwards in 2 hours, start to drip hydrochloric acid and adjust pH to 7, then be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained R-lyrica crude product 21.1g, and yield is 84.4%.Take the lyrica crude product 20g of will dry, Virahol and water are respectively 600g and 30g, start to be cooled to 0 ~ 10 DEG C of insulated and stirred 1.5h after being warming up to 80 DEG C, and suction filtration is dried and obtained R-lyrica 18g, purity 99.7%, isomer 0.01%, and yield is 90%.
Example 9:
Mother liquor concentrations thing 100g will be split, add water 120g, stir lower dropping hydrochloric acid and adjust pH to 3, suction filtration obtains educt 62g, ethyl acetate 180g is added in wet product, be warming up to 40 DEG C molten clear after be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained S-3-isobutylglutaric acid monoamide 54.8g, and yield is 77.6%.The S-3-isobutylglutaric acid monoamide 30g of oven dry is added in the four-hole boiling flask of 500ml, liquid caustic soda 60g, 25g bromine is dripped at being cooled to 10 DEG C, be warming up to 75 DEG C of insulations after dropwising and be cooled to 20 DEG C afterwards in 2 hours, start to drip hydrochloric acid and adjust pH to 7, then be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained R-lyrica crude product 21.1g, and yield is 84.4%.Take the lyrica crude product 20g of will dry, Virahol and water are respectively 80g and 50g, start to be cooled to 0 ~ 10 DEG C of insulated and stirred 2h after being warming up to 80 DEG C, and suction filtration is dried and obtained R-lyrica 18g, purity 99.8%, isomer 0.01%, and yield is 90%.
Example 10:
Mother liquor concentrations thing 100g will be split, add water 160g, stir lower dropping hydrochloric acid and adjust pH to 4, suction filtration obtains educt 58g, ethyl acetate 120g is added in wet product, be warming up to 45 DEG C molten clear after be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained S-3-isobutylglutaric acid monoamide 55.1g, and yield is 78.0%.The S-3-isobutylglutaric acid monoamide 30g of oven dry is added in the four-hole boiling flask of 500ml, liquid caustic soda 60g, 21g bromine is dripped at being cooled to 10 DEG C, be warming up to 75 DEG C of insulations after dropwising and be cooled to 20 DEG C afterwards in 2 hours, start to drip hydrochloric acid and adjust pH to 7, then be cooled to 5 DEG C of insulated and stirred 1 hour, suction filtration is dried and is obtained R-lyrica crude product 19.7g, and yield is 78.8%.Take the lyrica crude product 20g of will dry, Virahol and water are respectively 160g and 50g, start to be cooled to 0 ~ 10 DEG C of insulated and stirred 1h after being warming up to 80 DEG C, and suction filtration is dried and obtained R-lyrica 18.5g, purity 99.8%, isomer N.D%, and yield is 92.5%.
Claims (9)
1. prepare a method for lyrica isomer R-lyrica, it is characterized in that comprising the following steps:
1) 3-isobutylglutaric acid monoamide is used R-phenylethylamine split after mother liquor concentrations thing to add water and hydrochloric acid dissociates;
2) educt obtained above is added ethyl acetate refining, dry and obtain S-3-isobutylglutaric acid monoamide;
3) S-3-isobutylglutaric acid monoamide is dropped in liquid caustic soda system, drip bromine, lower the temperature again after rising to certain temperature;
4) start to drip hydrochloric acid and adjust pH to 6 ~ 8, be cooled to 0 ~ 10 DEG C of crystallization and obtain R-lyrica crude product;
5) dropped into by R-lyrica in the system of isopropyl alcohol and water, rise to certain temperature insulated and stirred, then be down to certain temperature crystallization, suction filtration is dried and is obtained R-lyrica.
2. the method preparing lyrica isomer R-lyrica according to claim 1, it is characterized in that R-phenylethylamine described in step 1) split after mother liquor concentrations thing refer to add compound 3-isobutylglutaric acid monoamide in chloroform and alcohols mixed system, drip suction filtration after resolving agent R-phenylethylamine splits and also filtrate concentrated the dry mother liquor concentrations thing obtained.
3. the method preparing lyrica isomer R-lyrica according to claim 1, it is characterized in that weight that step 1) adds water is 1 ~ 2 times of enriched material weight, the amount of hydrochloric acid is as the criterion with pH, and pH is 1 ~ 4.
4. the method preparing lyrica isomer R-lyrica according to claim 1, is characterized in that step 2) in the weight of ethyl acetate be 1 ~ 4 times of wet product S-3-isobutylglutaric acid monoamide weight.
5. the method preparing lyrica isomer R-lyrica according to claim 1, is characterized in that step 2) described in treating process in educt to add the molten clear temperature of ethyl acetate be 40 ~ 45 DEG C, the temperature of stirring and crystallizing is 0 ~ 10 DEG C afterwards.
6. the method preparing lyrica isomer R-lyrica according to claim 1, is characterized in that the liquid caustic soda weight added in step 3) is 2 ~ 4 times of S-3-isobutylglutaric acid monoamide weight; The weight of bromine is 0.7 ~ 0.9 times of S-3-isobutylglutaric acid monoamide weight.
7. the method preparing lyrica isomer R-lyrica according to claim 1, is characterized in that step 3) rises to certain temperature and refers to 70 ~ 80 DEG C, is down to certain temperature and refers to 20 ~ 30 DEG C.
8. the method preparing lyrica isomer R-lyrica according to claim 1, is characterized in that step 5) Virahol: water: the weight ratio of lyrica crude product three is 8:4:1 ~ 2:2:1.
9. the method preparing lyrica isomer R-lyrica according to claim 1, is characterized in that described step 5) is warming up to certain temperature and refers to 70 ~ 80 DEG C, is down to certain temperature crystallization and refers to 0 ~ 10 DEG C, and the time of insulation crystallization refers to 1 ~ 2 hour.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481712A (en) * | 2015-11-30 | 2016-04-13 | 常州市阳光药业有限公司 | Racemization recycling method of Pregabalin intermediate mother liquor from resolution |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0828704B1 (en) * | 1995-06-02 | 2002-03-13 | Warner-Lambert Company | Methods of making (s)-3-(aminomethyl)-5-methylhexanoic acid |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0828704B1 (en) * | 1995-06-02 | 2002-03-13 | Warner-Lambert Company | Methods of making (s)-3-(aminomethyl)-5-methylhexanoic acid |
Non-Patent Citations (1)
| Title |
|---|
| 黄燕: "普瑞巴林的合成工艺研究", 《浙江大学硕士学位论文》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481712A (en) * | 2015-11-30 | 2016-04-13 | 常州市阳光药业有限公司 | Racemization recycling method of Pregabalin intermediate mother liquor from resolution |
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